ABSTRACT Systemic lupus erythematosus (SLE) is an autoimmune disease that affects approximately 0.1% of the population and causes substantial morbidity and reduced lifespan. Current treatment is largely based on non- specific immunosuppression which is often only partially effective and may have serious side-effects. The development of more specific, effective and safer therapies is urgently needed. Polymorphisms in the transcription factor interferon regulatory factor 5 (IRF5) are strongly associated in human genetic studies with an increased risk of developing SLE and other autoimmune diseases. IRF5 plays an important role in Toll-like receptor signaling. Deficiency of IRF5 markedly reduces disease severity in a number of mouse models of SLE. Taken together, this suggests that IRF5 inhibition may be an effective therapeutic approach in SLE. The goal of this project is to obtain detailed information about IRF5 function and activation that will lead to a better understanding of the basic mechanisms underlying SLE pathogenesis and potentially to new approaches to inhibit IRF5 and the identification of novel therapeutic targets. This will be done by: (1) determining the IRF5- expressing cell type(s) responsible for mediating disease in a mouse model of SLE by deleting IRF5 in specific immune cell types and evaluating the effect of the deletion on disease development; (2) determining whether deletion of IRF5 after disease is established can reverse disease or prevent disease progression in a mouse model of SLE; (3) using the complementary approaches of retrogenic technology and CRISPR gene editing to create novel mouse models to determine the specific phosphorylation site(s) in IRF5 required for lupus pathogenesis in vivo and for IRF5 function and activation in primary immune cells ex vivo; (4) determining how the IRF5 polymorphisms associated with lupus risk modulate IRF5 expression and function in human myeloid dendritic cells. This will be done by making induced pluripotent stem (iPS) cells from peripheral blood mononuclear cells of healthy volunteers with and without the IRF5 risk polymorphisms and then differentiating the iPS cells into myeloid dendritic cells using a novel in vitro technique. In addition, in order to definitively determine the effect of the IRF5 risk polymorphisms, the polymorphisms will be introduced into non- polymorphic iPS cells using gene editing and functional IRF5 responses will be compared in isogenic myeloid dendritic cells that are genetically identical, except for the risk polymorphism of interest.